Ablation of prostaglandin E<sub>2</sub> signalling through dual receptor knockout in CAR T cells enhances therapeutic efficacy in solid tumours.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41673138.
- Also identified by DOI 10.1038/s41551-025-01610-6 and PMC identifier 13099425.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The efficacy of chimeric antigen receptor (CAR) T cell therapy in solid cancers is limited by immunosuppression in the tumour microenvironment (TME). Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) is a key factor locally inhibiting T cell function. We hypothesized that targeted ablation of PGE<sub>2</sub> signalling in CAR T cells may enhance their activity in PGE<sub>2</sub>-rich solid tumours. Here we generate knockout CAR T cells double deficient for the PGE<sub>2</sub> receptors EP2 and EP4 (EP2<sup>-/-</sup>EP4<sup>-/-</sup>) by CRISPR-Cas9 engineering. EP2<sup>-/-</sup>EP4<sup>-/-</sup> CAR T cells expanded unabatedly in the presence of PGE<sub>2</sub>. Further, they effectively controlled syngeneic and human xenograft tumour models in vivo, which was accompanied by intratumoural accumulation and persistence of modified T cells. Improved anti-tumour activity was also observed against patient-derived tumour samples from patients with pancreatic ductal adenocarcinoma (PDAC), colorectal (CRC) and neuroendocrine (NET) cancer. Our data uncovers the detrimental impact of PGE<sub>2</sub>-mediated suppression on CAR T cell efficacy and highlights EP2 and EP4 targeting as a potential strategy.
Medical subject headings
- Dinoprostone
- Receptors, Prostaglandin E, EP4 Subtype
- Signal Transduction
- Receptors, Prostaglandin E, EP2 Subtype
- Receptors, Chimeric Antigen
- Immunotherapy, Adoptive
- T-Lymphocytes
- Neoplasms